Leading researcher seeks to understand molecular basis of stress and resilience in the brain

From The Quarterly, Fall 2011

One of the most remarkable facts about depression is that it remains a “syndrome” ─ a list of symptoms, as opposed to a defined “disease” like Huntington’s disease or AIDS. Depression usually can be recognized by trained mental health professionals, but one decade into the 21st century, modern medicine still has no objective scientific test ─ a blood test, for instance, or diagnostic brain scan ─ that can determine instantly if a person is clinically depressed.

This fact is “humbling” and “a powerful motivating force” for Brain & Behavior Research Foundation Scientific Council Member and 1996 NARSAD Distinguished Investigator Grantee Eric Nestler, M.D., Ph.D. One of the world’s most innovative and productive investigators of the brain, he has devoted his career – first at Yale, then UT Southwestern in Dallas, and since 2008 at the Mount Sinai School of Medicine in NYC ─ to the study of addiction and depression. Yet with hundreds of scientific publications to his name, and widely honored by his peers (elected to the prestigious Institute of Medicine and the American Academy of Arts and Sciences), he remains dissatisfied and restless as he and his colleagues seek to solve the scientific problems that depression and addiction represent.

“Only by understanding depression and addiction at the molecular, genetic and epigenetic levels can we devise treatments that address their root causes, not merely their symptoms.”

“From a clinical point of view,” Dr. Nestler asserts, “there is only one thing that matters, and that is empirically making a patient feel better.” And he is “totally agnostic” about the means ─ whether it is psychotherapy, medication, or something else ─ of getting to this endpoint. He is passionate about the need to develop much more effective treatments for depression and addiction, since those we have today are not able to help every patient.

Depression and addiction may seem very different, but as Dr. Nestler explains, a “eureka moment” in 1998 enabled his team to recognize that the pathology of both, while imperfectly understood, in fact converges in part on cellular pathways and centers in the brain that control rewards. In a series of experiments in mice that involved preventing reward circuitry from becoming activated in response to cocaine, Dr. Nestler realized that “we could go further and push the animal to the point where it would become anhedonic,” i.e., unable to feel pleasure in situations where pleasure centers of the brain should normally be engaged. Anhedonia is experienced by most depressed people.

This seminal finding was only a beginning. Among other things, it led Dr. Nestler and colleagues to work extensively on ways of modeling depression in mice. The problem was: How can you know if a mouse is depressed? Since there’s no test or scan that can say whether a person is depressed, the problem is even more formidable in an animal. When he turned his attention to the problem in the 1990s, existing models of depression hinged on measuring an animal’s response to stress, typically short-term stress. Dr. Nestler believed these models were flawed and was determined to improve upon them. This is the kind of inquiry ─ high-risk, potentially high-reward ─ that NARSAD, now the Brain & Behavior Research Foundation, has long encouraged, he notes.

“NARSAD Grants have done a fabulous job in seeding the field of psychiatry with great junior investigators. I was fortunate in the late ’90s to receive a Distinguished Investigator Grant, which enabled me to do some high-risk work, for which I was appreciative. But I’ve seen the impact NARSAD has made far more broadly than just what has affected me personally.”

In his efforts to make a rodent model of depression closer to that seen in people, Dr. Nestler tried adapting a stress model called “social defeat,” which involved systematically exposing smaller, weaker individuals to larger, more aggressive ones. Precautions were taken to insure the weaker animals were physically unharmed; yet it was important that they be intimidated by their physical superiors.

Stressed in this manner over a period of 10 days, most of the weaker mice displayed symptoms closely resembling those reported by depressed people. They lost the ability to experience pleasure, as measured by their appetite for treats and for sex; they were anxious; and they were socially avoidant. They not only recoiled from contact with the individuals who dominated them; more significant to Dr. Nestler, they shunned contact even with “their own brothers, with which they’d been raised,” and had previously frolicked. Some of the defeated mice grew obese, compulsively stuffing themselves while showing fewer signs of enjoying their binges. But just as important, some of the mice exposed to intimidating stress did not develop any of these symptoms. “These mice were resilient, similar to the majority of people subjected to stress who don’t become clinically depressed.”

”NARSAD Grants have done a fabulous job in seeding the field of psychiatry with great junior investigators.”

Having a model that yielded both depressed and resilient mice “proved to be a very valuable tool,” which enabled Dr. Nestler and his team to “plunge deep into various areas of the brain to identify molecular changes that chronic stress induces, and also to find molecular changes mediating resilience.” These studies have yielded striking results: changes in molecules within nerve cells that correlate with the onset of stress-related depression. The researchers also found that resilience was not simply an absence of negative changes caused by stress, but rather “a whole set of separate changes that actually protect the animal.”

These experiments went beyond merely associating molecular changes with the presence or absence of depression; the work, importantly, makes causal connections. One is BDNF, or brain-derived neurotrophic factor, an essential protein in nerve cells that acts as a growth stimulator. Dr. Nestler’s work on BDNF extends from the protein itself, acting on nerve cell development, all the way “down” to molecular changes that ultimately can impact whether a mouse, and presumably a person, will become depressed in response to chronic stress, as modeled in “social defeat.”

Dr. Nestler’s team has discovered ways of manipulating BDNF. They can raise or lower its levels within a cell; but they can also go inside the cell nucleus and alter levels of regulatory molecules that determine how much BDNF a cell produces. Either way, they can make a healthy mouse depressed or a depressed mouse resilient. The process works in both directions, and, in this example, it works by either adjusting BDNF levels or levels of a gene-regulating “transcription factor” called CREB. The team has demonstrated the same reversibility with several other molecules. One is another growth-stimulating protein called WNT, which acts inside the nucleus via a transcription factor called beta-catenin. “If we inhibit the WNT-beta-catenin pathway in mice, we make them susceptible to depression; if we enhance the pathway, we enhance resilience.”

The next challenge is to design new and more effective drugs to treat depression (and addiction, whose mechanisms Dr. Nestler’s team has shown to be similarly sensitive to levels of gene expression). One approach involves making lists of genes that are either more or less active than normal in resilient mice and comparing these with genes more or less active than normal in depressed mice.

One set of studies has led to a search for regulators of tiny pores called ion channels in the membranes of nerve cells that control whether they will respond to an incoming signal. Dr. Nestler and his colleague at Mount Sinai, Dr. Ming-Hu Han, want to see if a list of existing molecules already available to drug developers overlaps with various molecular regulators of ion channels. Some of these may have antidepressant activity, and experiments are ongoing at Mount Sinai and elsewhere to see if this can be demonstrated in animal models. Further, another Mount Sinai colleague, Dr. Scott Russo, has been studying mechanisms involved in the cellular response to inflammation, and hypothesizes that some of these mechanisms may yield molecules that are especially active during depression. This could yield a biomarker for at least some types of depression ─ a signal in the blood that might, at last, definitively indicate the presence or absence of the illness in a simple blood test. Both Drs. Han and Russo were recipients of NARSAD Young Investigator Grants, which were instrumental in jump-starting their careers.

“From a clinical point of view, there is only one thing that matters, and that is empirically making a patient feel better.”

Dr. Nestler is deeply impressed with the complexity of the systems that regulate what he has called “the molecules of mood.” Yet in the end, he says, his work is about translating basic science into new and better treatments. “This is why we plunge deeper and deeper into the pathophysiology. Only by understanding depression and addiction at the molecular, genetic and epigenetic levels can we devise treatments that address their root causes, not merely their symptoms.”